Malate salt of N-(4-{[6,7-bis(methyloxy) quinolin-4-yl]oxy}phenyl)-N&#39;-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, and crystalline forms thereof for the treatment of cancer

ABSTRACT

Disclosed are malate salts of N-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclo-propane-1,1-dicarboxamide, including a (L)-malate salt, a (D)-malate salt, a (DL) malate salt, and mixtures thereof; and crystalline and amorphous forms of the malate salts. Also disclosed are pharmaceutical compositions comprising at least one malate salts of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide; and methods of treating cancer comprising administering at least one malate salt of N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1, 1-dicarboxamide.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. provisional application61/145,421, filed Jan. 16, 2009, which is incorporated herein byreference.

TECHNICAL FIELD

This disclosure relates to malate salts ofN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand to crystalline and amorphous forms of the malate salts ofN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.The malate salts ofN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideinclude one of (1) the (L)-malate salt, (2) the (D)-malate salt, (3) the(D,L)-malate salt, and (4) mixtures thereof. The disclosure also relatesto pharmaceutical compositions comprising at least one malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide.

The disclosure also relates to pharmaceutical compositions comprising acrystalline or an amorphous form of at least one malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide.

The disclosure also relates to methods of treating cancer comprisingadministering at least one malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

The disclosure further relates to methods of treating cancer comprisingadministering a crystalline or an amorphous form of at least one malatesalt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

BACKGROUND

Traditionally, dramatic improvements in the treatment of cancer areassociated with identification of therapeutic agents acting throughnovel mechanisms. One mechanism that can be exploited in cancertreatment is the modulation of protein kinase activity because signaltransduction through protein kinase activation is responsible for manyof the characteristics of tumor cells. Protein kinase signaltransduction is of particular relevance in, for example, thyroid,gastric, head and neck, lung, breast, prostate, and colorectal cancers,as well as in the growth and proliferation of brain tumor cells.

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases are comprised of a large number oftransmembrane receptors with diverse biological activity. For a detaileddiscussion of the receptor-type tyrosine kinases, see Plowman et al.,DN&P 7(6): 334-339, 1994. Since protein kinases and their ligands playcritical roles in various cellular activities, deregulation of proteinkinase enzymatic activity can lead to altered cellular properties, suchas uncontrolled cell growth associated with cancer. In addition tooncological indications, altered kinase signaling is implicated innumerous other pathological diseases, including, for example,immunological disorders, cardiovascular diseases, inflammatory diseases,and degenerative diseases. Therefore, protein kinases are attractivetargets for small molecule drug discovery. Particularly attractivetargets for small-molecule modulation with respect to antiangiogenic andantiproliferative activity include receptor type tyrosine kinases Ret,c-Met, and VEGFR2.

The kinase c-Met is the prototypic member of a subfamily ofheterodimeric receptor tyrosine kinases (RTKs) which include Met, Ronand Sea. The endogenous ligand for c-Met is the hepatocyte growth factor(HGF), a potent inducer of angiogenesis. Binding of HGF to c-Met inducesactivation of the receptor via autophosphorylation resulting in anincrease of receptor dependent signaling, which promotes cell growth andinvasion. Anti-HGF antibodies or HGF antagonists have been shown toinhibit tumor metastasis in vivo (See: Maulik et al Cytokine & GrowthFactor Reviews 2002 13, 41-59). c-Met, VEGFR2 and/or Ret overexpressionhas been demonstrated on a wide variety of tumor types including breast,colon, renal, lung, squamous cell myeloid leukemia, hemangiomas,melanomas, astrocytic tumor (which includes glioblastoma, giant cellglioblastoma, gliosarcoma, and glioblastoma with oligodendroglialcomponents). The Ret protein is a transmembrane receptor with tyrosinekinase activity. Ret is mutated in most familial forms of medullarythyroid cancer. These mutations activate the kinase function of Ret andconvert it into an oncogene product.

Inhibition of EGF, VEGF and ephrin signal transduction will prevent cellproliferation and angiogenesis, two key cellular processes needed fortumor growth and survival (Matter A. Drug Disc. Technol. 20016,1005-1024). Kinase KDR (refers to kinase insert domain receptor tyrosinekinase) and flt-4 (fms-like tyrosine kinase-4) are both vascularendothelial growth factor (VEGF) receptors. Inhibition of EGF, VEGF andephrin signal transduction will prevent cell proliferation andangiogenesis, two key cellular processes needed for tumor growth andsurvival (Matter A. Drug Disc. Technol. 20016, 1005-1024). EGF and VEGFreceptors are desirable targets for small molecule inhibition.

Accordingly, small-molecule compounds that specifically inhibit,regulate and/or modulate the signal transduction of kinases,particularly including Ret, c-Met and VEGFR2 described above, areparticularly desirable as a means to treat or prevent disease statesassociated with abnormal cell proliferation and angiogenesis. One suchsmall-molecule isN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,which has the chemical structure:

WO 2005/030140 describes the synthesis ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(Example 12, 37, 38, and 48) and also discloses the therapeutic activityof this molecule to inhibit, regulate and/or modulate the signaltransduction of kinases, (Assays, Table 4, entry 289). Example 48 is onparagraph [0353] in WO 2005/030140.

Besides therapeutic efficacy, the drug developer endeavors to provide asuitable form of the therapeutic agent that has properties relating toprocessing, manufacturing, storage stability, and/or usefulness as adrug. Accordingly, the discovery of a form that possesses some or all ofthese desired properties is vital to drug development.

Applicants have found a salt form of the drugN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidethat has suitable properties for use in a pharmaceutical composition forthe treatment of a proliferative disease such as cancer. The novel saltform of the invention exists in crystalline and amorphous forms

SUMMARY

This disclosure relates to malate salts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas described herein, pharmaceutical compositions thereof as describedherein, and uses thereof as described herein.

Another aspect relates to crystalline and amorphous forms of the malatesalts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideas described herein, pharmaceutical compositions thereof as describedherein, and uses thereof as described herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the experimental XRPD pattern for crystalline Compound (I),Form N-1 at 25° C.

FIG. 2 shows the solid state ¹³C NMR spectrum of crystalline Compound(I), Form N-1.

FIG. 3 shows the solid state ¹⁵N NMR spectrum of crystalline Compound(I), Form N-1.

FIG. 4 shows the solid state ¹⁹F NMR spectrum of crystalline Compound(I), Form N-1.

FIG. 5 shows the thermal gravimetric analysis (TGA) of crystallineCompound (I), Form N-1.

FIG. 6 shows the differential scanning calorimetry (DSC) of crystallineCompound (I), Form N-1.

FIG. 7 shows the moisture sorption of crystalline Compound (I), FormN-1.

FIG. 8 shows the experimental XRPD pattern for crystalline Compound (I),Form N-2 at 25° C.

FIG. 9 shows the solid state ¹³C NMR spectrum of crystalline Compound(I), Form N-2.

FIG. 10 shows the solid state ¹⁵N NMR spectrum of crystalline Compound(I), Form N-2.

FIG. 11 shows the solid state ¹⁹F NMR spectrum of crystalline Compound(I), Form N-2.

FIG. 12 shows the thermal gravimetric analysis (TGA) of crystallineCompound (I), Form N-2.

FIG. 13 shows the differential scanning calorimetry (DSC) of crystallineCompound (I), Form N-2.

FIG. 14 shows the moisture sorption of crystalline Compound (I), FormN-2.

FIG. 15 shows the experimental and simulated XRPD patterns forcrystalline Compound (III), Form N-1 at room temperature.

FIG. 16 shows the solid state ¹³C NMR spectrum of crystalline Compound(III), Form N-1.

FIG. 17 shows the solid state ¹⁵N NMR spectrum of crystalline Compound(III), Form N-1.

FIG. 18 shows the solid state ¹⁹F NMR spectrum of crystalline Compound(III), Form N-1.

FIG. 19 shows the thermal gravimetric analysis (TGA) of crystallineCompound (III), Form N-1.

FIG. 20 shows the differential scanning calorimetry (DSC) of crystallineCompound (III), Form N-1.

FIG. 21 shows the moisture sorption of crystalline Compound (III), FormN-1.

FIG. 22 shows the XRPD pattern of amorphous Compound (I) at roomtemperature.

FIG. 23 shows the solid state ¹³C NMR spectrum of amorphous Compound(I).

FIG. 24 shows the solid state ¹⁵N NMR spectrum of amorphous Compound(I).

FIG. 25 shows the solid state ¹⁹F NMR spectrum of amorphous Compound(I).

FIG. 26 shows the differential scanning calorimetry (DSC) of amorphousCompound (I).

FIG. 27 shows the moisture sorption of amorphous Compound (I).

DETAILED DESCRIPTION

This disclosure relates to improvements of the physiochemical propertiesofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,whereby this compound may be suitable for drug development. Disclosedherein are malate salts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.New solid state forms of those salts are also disclosed. The malatesalts as well as their crystalline and amorphous forms disclosed hereineach represent separate aspects of the disclosure. Although the malatesalts and their solid state forms are described herein, the inventionalso relates to novel compositions containing the disclosed salts andsolid state forms. Therapeutic uses of the salts and solid state formsdescribed as well as therapeutic compositions containing them representseparate aspects of the disclosure. The techniques used to characterizethe salts and their solid state forms are described in the examplesbelow. These techniques, alone or in combination, may be used tocharacterize the salts and their solid state forms disclosed herein. Thesalts and their solid state forms may be also characterized by referenceto the disclosed figures.

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamidewas found to have an enzyme Ret IC₅₀ value of about 5.2 nM (nanomolar)and an enzyme c-Met IC₅₀ value of about 1.3 nM (nanomolar). The assaythat was used to measure this c-Met activity is described in paragraph[0458] in WO2005-030140.

RET biochemical activity was assessed using a Luciferase-CoupledChemiluminescent Kinase assay (LCCA) format as described inWO2005-030140. Kinase activity was measured as the percent ATP remainingfollowing the kinase reaction. Remaining ATP was detected byluciferase-luciferin-coupled chemiluminescence. Specifically, thereaction was initiated by mixing test compounds, 2 M ATP, 1 M poly-EYand 15 nM RET (baculovirus expressed human RET kinase domain M700-D1042with a (His)₆ tag on the N-terminus) in a 20 uL assay buffer (20 mMTris-HCL pH 7.5, 10 mM MgCl₂, 0.01% Triton X-100, 1 mM DTT, 3 mM MnCl₂).The mixture was incubated at ambient temperature for 2 hours after which20 uL luciferase-luciferin mix was added and the chemiluminescent signalread using a Wallac Victor² reader. The luciferase-luciferin mixconsists of 50 mM HEPES, pH 7.8, 8.5 ug/mL oxalic acid (pH 7.8), 5 mMDTT, 0.4% Triton X-100, 0.25 mg/mL coenzyme A, 63 μM AMP, 28 μg/mlluciferin and 40,000 units of light/mL luciferase.

Malate Salts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

This disclosure relates to malate salts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.These malate salts are a combination ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidewith malic acid which forms a 1:1 malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Malic acid has the following structure:

Due to its chiral carbon, two enantiomers of malic acid exist, (L)-malicacid and (D)-malic acid.

(L)-malic acid has the following structure:

There are various names or designations for the (L)-malic acid that areknown in the art. These include butanedioic acid, hydroxy-, (2S)-(9CI);butanedioic acid, hydroxy-, (S)-; malic acid, L-(8CI); malic acid,1-(3CI); (−)-(S)-malic acid; (−)-Hydroxysuccinic acid; (−)-(L)-malicacid; (−)-malic acid; (2S)-2-hydroxybutanedioic acid;(2S)-2-hydroxysuccinic acid; (S)-malic acid; apple acid; L-(−)-malicacid; (L)-malic acid; NSC 9232; S-(−)-malic acid; andS-2-hydroxybutanedioic acid.

(D) malic acid has the following structure:

There are various names or designations for the (D)-malic acid that areknown in the art. These include butanedioic acid, 2-hydroxy-, (2R)-,butanedioic acid, hydroxy-, (2R)-(9CI); butanedioic acid, hydroxy-,(R)-; (+)-malic acid; (2R)-2-hydroxybutanedioic acid; (2R)-malic acid;(R)-(+)-malic acid; (R)-malic acid; D-(+)-2-hydroxysuccinic acid;D-(+)-malic acid; and D-malic acid.

As discussed above, the chemical structure ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideis

There are no chiral carbons in its chemical structure. There are variousnames forN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidewhich are publicly known, and some of these various names ordesignations include 1,1-cyclopropanedicarboxamide,N′-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N-(4-fluorophenyl)- and1,1-cyclopropanedicarboxamide,N-[4-[(6,7-dimethoxy-4-quinolinyl)oxy]phenyl]-N′-(4-fluorophenyl)-(9CI).

N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidecan be prepared according to any of several different methodologies,either on a gram scale (<1 kg) or a kilogram scale (>1 kg). A gram-scalemethod is set forth in WO 2005-030140, which describes the synthesis ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(Examples 25, 37, 38, and 48), which is hereby incorporated byreference. Alternatively,N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,including the active compound(s), can be prepared on a kilogram scaleusing the procedure set forth in Example 1 below.

This disclosure relate to malate salts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide:

-   -   the (L)-malate salt of        N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,        (Compound (I));    -   the (D)-malate salt of        N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,        (Compound (II)); and    -   the (DL)-malate salt of        N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide        (Compound (III)).        Each has improved properties over        N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide        and its other salts. The names used herein to characterize a        specific form, e.g. “N-2” etc., are not to be limited so as to        exclude any other substance possessing similar or identical        physical and chemical characteristics, but rather such names are        used as mere identifiers that are to be interpreted in        accordance with the characterization information presented        herein.

The malate salts ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,and particularly Compound (I), have a preferred combination ofpharmaceutical properties for development. Under the conditions of 25°C./60% relative humidity (RH) and 40° C./60% RH, Compound (I) showed nochange in assay, purity, moisture and dissolution. The DSC/TGA showedthe Compound (I) to be stable up to 185° C. No solvent losses wereobserved. The uptake of water by the (L)-malate salt was reversible witha slight hysteresis. The amount of water taken up was calculated atabout 0.60 wt % at 90% RH. The (L)-malate salt was synthesized with goodyield and purity >90% and had sufficient solubility for use in apharmaceutical composition. The amount of water associated with thissalt was calculated at about 0.5 wt % by Karl Fischer analysis andcorrelates with TGA and GVS analysis. The (D)-malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide)will have the same properties as the (L)-malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide).

The Compound (I) salt itself, and separately its crystalline andamorphous forms, exhibit beneficial properties over the free base andthe other salts of theN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.For example, the hydrochloride salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideexhibits undesirable moisture sensitivity, changing phase upon exposureto high humidity (75% humidity) and high temperature (40° C.). Themaleate salt had low solubility. The tartrate salt had low crystallinityand low solubility. The phosphate salt exhibited an 8% weight gain dueto absorption of H₂O—the highest among the salts tested.

The water solubility of the various salts was determined using 10 mgsolids per mL water. The salts were prepared in a salt screen byreacting an acetone solution of the freebase with stock tetrahydrofuran(THF) solutions of a range of acids in about a 1:1 molar ratio. Table 1below summarizes the water solubility and other data relating to thefree base and each salt.

TABLE 1 Solubility (mg/ml) Free base <<0.001 very low solubilityPropionate <<0.001 no salt formation; mixture of free base and acidAcetate <<0.001 no salt formation; mixture of free base and acidSuccinate 0.010 no salt formation; mixture of free base and acidBenzoate 0.005 no salt formation; mixture of free base and acidL-Lactate 0.015 Amorphous, salt Pyrrogluta- 0.44 Amorphous, salt mateGlycolate 0.016 Amorphous, salt L- 0.053 low crystallinity AscorbateSulfate 0.004 Crystalline salt, low solubility Tosylate 0.007Crystalline salt, low solubility Malonate 0.003 Crystalline salt, lowsolubility 2,5dihy- <<0.001 Crystalline Salt, low solubility droxy-benzoate Fumarate 0.008 Crystalline Salt, low solubility Citrate 0.002Crystalline Salt, low solubility Mesylate 0.175 Crystalline Salt;possible sulfonic acid formation when made with alcohol Esylate 0.194Crystalline Salt; possible sulfonic acid formation when made withalcohol Benzene- 0.039 Crystalline Salt; possible sulfonic acidformation sulfonate when made with alcohol Chloride 0.070 Crystallinebut Hygroscopic; possible hydrate formation. Change in XRPD pattern uponexposure to humidity. Maleate 0.005 Crystalline salt, possible hydrateformation; low solubility; different XRPD pattern observed upon scale up(possible polymorphism issue) Phosphate 0.026 Crystalline butHygroscopic. L-Tartrate 0.014 Low degree of crystallinity; Hygroscopic.(L)-Malate 0.059 Crystalline; non-Hygroscopic with no indication ofhydrate formation. Suitable solubility, and chemical/physical stability.

Another aspect of this disclosure relates to crystalline forms ofCompound (I), which include the N-1 and/or the N-2 crystalline form ofCompound (I) as described herein. Each of form of Compound (I) is aseparate aspect of the disclosure. Similarly, another aspect of thisdisclosure relates to crystalline forms of Compound (II), which includethe N-1 and/or the N-2 crystalline form of Compound (II) as describedherein. Each of which is also a separate aspect of the disclosure. As isknown in the art, the crystalline (D) malate salt will form the samecrystalline form and have the same properties as crystalline Compound(I). See WO 2008/083319, which discusses the properties of crystallineenantiomers. Mixtures of the crystalline forms of Compounds (I) and (II)are another aspect of the disclosure.

The crystalline N-1 forms of Compounds (I) and (I) as described here maybe characterized by at least one of the following:

-   -   (i) a solid state ¹³C NMR spectrum with peaks at 18.1, 42.9,        44.5, 70.4, 123.2, 156.2, 170.8, 175.7, and 182.1 ppm, ±0.2 ppm;    -   (ii) a solid state ¹³C NMR spectrum substantially in accordance        with the pattern shown in FIG. 2;    -   (iii) an x-ray powder diffraction pattern (CuKα λ=1.5418 Å)        comprising four or more peaks selected from: 6.4, 9.0, 12.0,        12.8, 13.5, 16.9, 19.4, 21.5, 22.8, 25.1, and 27.6°2θ±0.2° 20,        wherein measurement of the crystalline form is at an ambient        room temperature;    -   (iv) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 1;    -   (v) a solid state ¹⁵N NMR spectrum with peaks at 118.6, 119.6,        120.7, 134.8, 167.1, 176.0, and 180 ppm, ±0.2 ppm; and/or    -   (vi) a solid state ¹⁵N NMR spectrum substantially in accordance        with the pattern shown in FIG. 3.

Other solid state properties which may be used to characterize thecrystalline N-1 forms of Compounds (I) and (II) are shown in the figuresand discussed in the examples below. For crystalline Compound (I), thesolid state phase and the degree of crystallinity remained unchangedafter exposure to 75% RH at 40° C. for 1 week.

The crystalline N-2 forms of Compounds (I) and (II) as described heremay be characterized by at least one of the following:

-   -   (i) a solid state ¹³C NMR spectrum with peaks at 23.0, 25.9,        38.0, 54.4, 56.11, 41.7, 69.7, 102.0, 122.5, 177.3, 179.3,        180.0, and 180.3, ±0.2 ppm;    -   (ii) a solid state ¹³C NMR spectrum substantially in accordance        with the pattern shown in FIG. 9;    -   (ii) an x-ray powder diffraction pattern (CuKα λ=1.5418 Å)        comprising four or more peaks selected from: 6.4, 9.1, 12.0,        12.8, 13.7, 17.1, 20.9, 21.9, 22.6, and 23.7 020 0.2° 20,        wherein measurement of the crystalline form is at an ambient        room temperature;    -   (iv) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 8;    -   (v) a solid state ¹⁵N NMR spectrum with peaks at 118.5, 120.8,        135.1, 167.3, and 180.1 ppm; and/or    -   (vi) a solid state ¹⁵N NMR spectrum substantially in accordance        with the pattern shown in FIG. 10.        Other solid state properties which may be used to characterize        the crystalline N-2 forms of Compounds (I) and (II) are shown in        the figures and discussed in the examples below.

In another embodiment, the disclosure relates to a crystalline form ofCompound (I), as described herein in any of the aspects and/orembodiments, is substantially pure N-1 form.

In another embodiment, the disclosure relates to a crystalline form ofCompound (I), as described herein in any of the aspects and/orembodiments, is substantially pure N-2 form.

The disclosure also relates to amorphous forms of Compounds (I) and(II). The preparation and solid state properties and characteristics ofthe amorphous foru of Compound (I) are described in the examples below.The amorphous forms of Compounds (I) and (II) represent another aspectof the disclosure.

One further aspect of the disclosure relates to mixtures of Compound (I)and Compound (II). The mixtures may have from greater than zero weight %to less than 100 weight % Compound (I) and from less than 100 weight %to greater zero weight % Compound (II), based on the total weight ofCompound (I) and Compound (II). In other embodiments, the mixturecomprises from about 1 to about 99 weight % Compound (I) and from about99 to about 1 weight % Compound (II), based on the total weight ofCompound (I) and Compound (II) in said mixture. In a further embodiment,the mixture comprises from about 90 weight % to less than 100 weight %Compound (I) and from greater than zero weight % to about 10 weight %Compound (II), based on the total weight of Compound (I) and Compound(II). Accordingly, the mixture may have 1-10% by weight of Compound (I);11-20% by weight of Compound (I); 21-30% by weight of Compound (I);31-40% by weight of Compound (I); 41-50% by weight of Compound (I);51-60% by weight of Compound (I); 61-70% by weight of Compound (I);71-80% by weight of Compound (I); 81-90% by weight of Compound (I); or91-99% by weight of Compound (I) with the remaining weight percentage ofmalate salt being that of Compound (II).

Another aspect of this disclosure relates to crystalline forms of(DL)-malate salt ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,Compound (III). The (DL)-malate salt is prepared from racemic malicacid. The crystalline N-1 form of Compound (III) as described here maybe characterized by at least one of the following:

-   -   (i) a solid state ¹³C NMR spectrum with four or more peaks        selected from 20.8, 26.2, 44.8, 55.7, 70.7, 100.4, 101.0, 114.7,        115.2, 116.0, 119.7, 120.4, 121.6, 124.4, 136.9, 138.9, 141.1,        145.7, 150.3, 156.5, 157.6, 159.6, 165.2, 167.4, 171.2, 176.3,        182.1 ppm, ±0.2 ppm;    -   (ii) a solid state ¹³C NMR spectrum substantially in accordance        with the pattern shown in FIG. 16;    -   (iii) a powder x-ray diffraction pattern (CuKα λ=1.5418 Å)        comprising four or more 2θ values selected from: 12.8, 13.5,        16.9, 19.4, 21.5, 22.8, 25.1, and 27.6, ±0.2°2θ, wherein        measurement of the crystalline form is at temperature of room        temperature;    -   (iv) an x-ray powder diffraction (XRPD) spectrum substantially        in accordance with the pattern shown in FIG. 15;    -   (v) a solid state ¹⁵N NMR spectrum with peaks at 119.6, 134.7,        and 175.5 ppm, ±0.2 ppm; and/or    -   (vi) a solid state ¹⁵N NMR spectrum substantially in accordance        with the pattern shown in FIG. 17.        Other solid state properties which may be used to characterize        the crystalline N-1 form of Compound (III) are shown in the        figures and discussed in the examples below. In one embodiment,        the N-1 Form of Compound (III) is characterized by unit cell        parameters approximately equal to the following:        Cell dimensions: a=14.60 Å    -   b=5.20 Å    -   c=39.09 Å    -   α=90.0°    -   β=90.4°    -   γ=90.0°        Space group: P2₁/n        Molecules of Compound (I)/unit cell: 4

Volume=2969 Å³

Density (calculated)=1.422 g/cm³The unit cell parameters of Form N-1 of Compound (III) were measured ata temperature of approximately 25° C., e.g., ambient or roomtemperature.

Each of the N-1 and N-2 crystalline forms of Compounds (I) and (II) andthe crystalline form N-1 of Compound (III) have unique characteristicsthat can distinguish them one from another. These characteristics can beunderstood by comparing the physical properties of the solid state formswhich are presented in the Examples below. For example, Table 2 listscharacteristic XRPD peak positions (°2θ±0.2°2θ) for crystalline Compound(III), Form N-1 and Forms N-1 and N-2 of crystalline Compound (I).Amorphous forms do not display reflection peaks in their XRPD patterns.

TABLE 2 Characteristic diffraction peak positions (degrees 2θ ± 0.2) @RT, based on pattern collected with a diffractometer (CuKα) with aspinning capillary. Compound (I) Compound (I) Compound (III) Form N-1Form N-2 Form N-1  6.4  6.4  6.4  9.0  9.1  9.1 12.0 12.0 12.1 12.8 12.812.8 13.5 13.7 13.6 16.9 17.1 17.1 19.4* 20.9* 19.3 21.5* 21.9* 21.422.8* 22.6 22.8 25.1* 23.7 25.1 27.6* — 27.6 *unique reflections betweenCompound (I), Form N-1 and Compound (I), Form N-2.The unique reflections between Forms N-1 and N-2 of crystalline Compound(II) are designated by an asterisk (*). As discussed above, Compound(II) is an enantiomer of Compound (I) and thus, Compound (II), Form N-1will have the same characteristic reflection pattern and unique peaks asthose listed in Table 2 for Compound (I), Form N-1. Likewise, Compound(II), Form N-2 will have the same characteristic reflection pattern andunique peaks as those listed in Table 2 for Compound (I), Form N-2.Compounds (I) and (II) are distinct from one another based on theirabsolute stereochemistry, i.e., the (L)-malate salt versus the(D)-malate salt, respectively. Crystalline Compound (III), Form N-1, isdistinct as the (D,L)-malate salt.

The characteristic peaks from the solid state NMR may also serve todistinguish the crystalline and amorphous forms disclosed herein. Forexample, Table 3 lists characteristic solid state ¹³C NMR peaks forcrystalline Compound (III), Form N-1; crystalline Compound (I), FormsN-1 and N-2, and the amorphous form of Compound (I).

TABLE 3 Solid State Carbon-13 NMR Resonances (ppm, ±0.2 ppm) (I) Form N-(I), Form N- (III), Form (I), 1 2 N-1 Amorphous 18.1 23.0 20.8 97.2 42.925.9 26.2 33.8 44.5 38.0 44.8 142.9 54.4 54.4 70.7 — 56.1 56.1 114.7 —70.4 41.7 141.1 — 123.2 69.7 145.7 — 156.2 102.0 176.3 — 170.8 122.5182.1 — 175.7 177.3 — — 182.1 179.3 — — — 180.0 — — — 180.3 — —The solid state ¹F and ¹⁵N NMR spectra, discussed below, provide datafor similar comparison and characterization. As discussed above, beingan enantiomer of Compound (I), crystalline Forms N-1 and N-2 and theamorphous form of Compound (II) will have the same solid state NMRresonances, and unique peaks between them, as those listed in Table 3for Forms N-1 and N-2 of crystalline Compound (I).

Pharmaceutical Compositions and Methods of Treatment

Another aspect of this disclosure relates to a pharmaceuticalcomposition comprising at least one of Compound (I), Compound (II),Compound (III), or combinations thereof, and a pharmaceuticallyacceptable excipient. The amount of Compound (I), Compound (II),Compound (III), or the combinations thereof in the pharmaceuticalcomposition can be a therapeutically effective amount. Compound (I),Compound (II), or Compound (III) may individually be present in thepharmaceutical composition as one of the solid state forms discussedabove or combinations thereof. The crystalline forms are preferred solidstate forms. Accordingly another aspect of this disclosure relates to asolid or dispersion pharmaceutical composition comprising at least oneof a therapeutically effective amount of a crystalline form of Compound(I), Compound (II), Compound (III), or combinations thereof, and apharmaceutically acceptable excipient.

Another aspect of this disclosure relates to a method of treating cancercomprising administering to a subject in need thereof at least one ofCompound (I), Compound (II), Compound (III) or combinations thereof. Theamount of Compound (I), Compound (II), or combinations thereofadministered can be a therapeutically effective amount. Compound (I),Compound (II), or Compound (III) may be individually administered as oneof the solid state forms discussed above or combinations thereof. Thecrystalline forms are preferred solid state forms, with crystallineCompound (I), Form N-1 or N-2 being preferred. Accordingly anotheraspect of this disclosure relates to a method of treating cancercomprising administering to a subject in need thereof a therapeuticallyeffective amount of at least one of Compound (I), Compound (II),Compound (III), or combinations thereof, wherein Compound (I), Compound(II), or Compound (III) is present in a crystalline form. In anotheraspect of this disclosure, the method of treatment may be practiced byadministering a pharmaceutical composition of at least one of Compound(I), Compound (II), Compound (III) or combinations thereof such asdiscussed above.

Another aspect of this disclosure relates to a method of treatingcancer, as discussed above, where the cancer treated is stomach cancer,esophageal carcinoma, kidney cancer, liver cancer, ovarian carcinoma,cervical carcinoma, large bowel cancer, small bowel cancer, brain cancer(including astrocytic tumor, which includes glioblastoma, giant cellglioblastoma, gliosarcoma, and glioblastoma with oligodendroglialcomponents), lung cancer (including non-small cell lung cancer), bonecancer, prostate carcinoma, pancreatic carcinoma, skin cancer, bonecancer, lymphoma, solid tumors, Hodgkin's disease, non-Hodgkin'slymphoma or thyroid cancer thyroid cancer (including medullary thyroidcancer).

Tyrosine kinase inhibitors have also been used to treat non-small celllung cancer (NSCLC). Gefitinib and erlotinib are angiogenesis inhibitorsthat target receptors of an epidermal growth factor called tyrosinekinase. Erlotinib and Gefitinib are currently being used for treatingNSCLC. Another aspect of this disclosure relates to a method of treatingnon-small cell lung cancer (NSCLC) in a subject, the method comprisingadministering to the subject in need of the treatment a therapeuticallyeffective amount ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,or a pharmaceutically acceptable salt thereof, optionally in combinationwith Erlotinib or Gefitinib. In another embodiment, the combination iswith Erlotinib.

Another aspect of this disclosure relates to a method of treatingnon-small cell lung cancer (NSCLC) in a subject, the method comprisingadministering to the subject in need of the treatment a therapeuticallyeffective amount of Erlotinib or Gefitinib in combination with at leastone of Compound (I), Compound (II), Compound (III) or combinationsthereof. Compound (I), Compound (II), or Compound (III) may beindividually administered as one of the solid state forms discussedabove or combinations thereof. The crystalline forms are preferred solidstate forms. Accordingly another aspect of this disclosure relates to amethod of treating a method of treating non-small cell lung cancer(NSCLC) in a subject, the method comprising administering to the subjectin need of the treatment a therapeutically effective amount of Erlotinibor Gefitinib in combination with at least one of Compound (I), Compound(II), Compound (III), or combinations thereof, wherein Compound (I),Compound (II), or Compound (III) is present in a crystalline form. Inanother aspect of this disclosure, this method of treatment may bepracticed by administering a pharmaceutical composition of at least oneof Compound (I), Compound (II), Compound (III) or combinations thereofsuch as discussed above. In another embodiment, the combinationadministered in this method is Erlotinib with at least one of Compound(I), Compound (II), Compound (III), or combinations thereof.

Another aspect of this disclosure relates to a method of treating anastrocytic tumor (which includes glioblastoma, giant cell glioblastoma,gliosarcoma, and glioblastoma with oligodendroglial components in asubject) in a subject, the method comprising administering to thesubject in need of the treatment a therapeutically effective amount ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

Another aspect of this disclosure relates to a method of treating anastrocytic tumor (which includes glioblastoma, giant cell glioblastoma,gliosarcoma, and glioblastoma with oligodendroglial components in asubject) in a subject, the method comprising administering to thesubject in need of the treatment a therapeutically effective amount ofat least one of Compound (I), Compound (II), Compound (III) orcombinations thereof. Compound (I), Compound (II), or Compound (III) maybe individually administered as one of the solid state forms discussedabove or combinations thereof. The crystalline forms are preferred solidstate forms. Accordingly another aspect of this disclosure relates to amethod of treating an astrocytic tumor comprising administering to asubject in need thereof a therapeutically effective amount of at leastone of Compound (I), Compound (II), Compound (III), or combinationsthereof, wherein Compound (I), Compound (II), or Compound (III) ispresent in a crystalline form. In another aspect of this disclosure,this method of treatment may be practiced by administering apharmaceutical composition of at least one of Compound (I), Compound(II), Compound (III) or combinations thereof such as discussed above.

Another aspect of this disclosure relates to a method of treatingthyroid cancer (including medullary thyroid cancer) in a subject, themethod comprising administering to the subject in need of the treatmentN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,or a pharmaceutically acceptable salt thereof. The amount administeredcan be a therapeutically effective amount.

Another aspect of this disclosure relates to a method of treatingthyroid cancer (including medullary thyroid cancer) in a subject, themethod comprising administering to the subject in need of the treatmentat least one of Compound (I), Compound (II), Compound (III) orcombinations thereof. Compound (I), Compound (II), or Compound (III) maybe individually administered as one of the solid state forms discussedabove or combinations thereof. The crystalline forms are preferred solidstate forms. Accordingly another aspect of this disclosure relates to amethod of treating thyroid cancer comprising administering to a subjectin need thereof a therapeutically effective amount of at least one ofCompound (I), Compound (II), Compound (III), or combinations thereof,wherein Compound (I), Compound (II), or Compound (IT) is present in acrystalline form. In another aspect of this disclosure, this method oftreatment may be practiced by administering a pharmaceutical compositionof at least one of Compound (I), Compound (II), Compound (III) orcombinations thereof such as discussed above.

Another aspect of this disclosure relates to a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities. This method administers, to a subject inneed thereof, at least one of Compound (I), Compound (II), Compound(III) or combinations thereof. The amount of Compound (I), Compound(II), or combinations thereof administered can be a therapeuticallyeffective amount. Compound (I), Compound (II), or Compound (III) may beindividually administered as one of the solid state forms discussedabove or combinations thereof. The crystalline forms are preferred solidstate forms.

Accordingly another aspect of this disclosure relates to a method oftreating diseases or disorders associated with uncontrolled, abnormal,and/or unwanted cellular activities comprising administering to asubject in need thereof a therapeutically effective amount of at leastone of Compound (I), Compound (II), Compound (III), or combinationsthereof, wherein Compound (I), Compound (II), or Compound (III) ispresent in a crystalline form. In another aspect of this disclosure,this method of treatment may be practiced by administering apharmaceutical composition of at least one of Compound (I), Compound(I), Compound (III) or combinations thereof such as discussed above.Another aspect of this disclosure relates to a method of treatingdiseases or disorders associated with uncontrolled, abnormal, and/orunwanted cellular activities. This method administers, to a subject inneed thereof, a crystalline form of Compound (I), Compound (II), or anycombination of Compound (I) and (II). The amount of Compound (I),Compound (II), or any combination of Compound (I) and (II) administeredcan be a therapeutically effective amount.

Another aspect of this disclosure relates to a use of theN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt according to any of theabove embodiments for the manufacture of a medicament for the treatmentof a disease or disorder discussed above. When dissolved, a crystallineor amorphous form according to this disclosure loses its solid statestructure, and is therefore referred to as a solution of, for example,Compound (I). At least one crystalline form disclosed herein may be usedto prepare at least one liquid formulation in which at least onecrystalline form according to the disclosure is dissolved and/orsuspended.

A pharmaceutical composition such as discussed above may be anypharmaceutical form which contains active Compound (I), Compound (II)and/or Compound (III), including the solid state forms thereof(hereinafter referred to as active compound(s). The pharmaceuticalcomposition may be, for example, a tablet, capsule, liquid suspension,injectable, topical, or transdermal. The pharmaceutical compositionsgenerally contain about 1% to about 99% by weight of the activecompound(s), or a crystalline form of the active compound(s), and 99% to1% by weight of a suitable pharmaceutical excipient. In one example, thecomposition will be between about 5% and about 75% by weight of activecompound, with the rest being suitable pharmaceutical excipients orother adjuvants, as discussed below.

A “therapeutically effective amount of the active compounds, or acrystalline or amorphous form of the active compound(s), according tothis disclosure to inhibit, regulate and/or modulate the signaltransduction of kinases (discussed here concerning the pharmaceuticalcompositions) refers to an amount sufficient to treat a patientsuffering from any of a variety of cancers associated with abnormal cellproliferation and angiogenesis. A therapeutically effective amountaccording to this disclosure is an amount therapeutically useful for thetreatment or prevention of the disease states and disorders discussedherein. Compounds (I), (II), and/or (III) (including their solid stateforms), possess therapeutic activity to inhibit, regulate and/ormodulate the signal transduction of kinases such as described inWO2005-030140.N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide.

The actual amount required for treatment of any particular patient willdepend upon a variety of factors including the disease state beingtreated and its severity; the specific pharmaceutical compositionemployed; the age, body weight, general health, sex and diet of thepatient; the mode of administration; the time of administration; theroute of administration; and the rate of excretion of the activecompound(s), or a crystalline form of the active compound(s), accordingto this disclosure; the duration of the treatment; any drugs used incombination or coincidental with the specific compound employed; andother such factors well known in the medical arts. These factors arediscussed in Goodman and Gilman's “The Pharmacological Basis ofTherapeutics”, Tenth Edition, A. Gilman, J. Hardman and L. Limbird,eds., McGraw-Hill Press, 155-173, 2001, which is incorporated herein byreference. The active compound(s), or a crystalline form of activecompound(s), according to this disclosure and pharmaceuticalcompositions comprising them, may be used in combination with anticanceror other agents that are generally administered to a patient beingtreated for cancer. They may also be co-formulated with one or more ofsuch agents in a single pharmaceutical composition.

Depending on the type of pharmaceutical composition, thepharmaceutically acceptable carrier may be chosen from any one or acombination of carriers known in the art. The choice of thepharmaceutically acceptable carrier depends partly upon the desiredmethod of administration to be used. For a pharmaceutical composition ofthis disclosure, that is, one of the active compound(s), or acrystalline form of the active compound(s), of this disclosure, acarrier should be chosen so as to substantially maintain the particularform of the active compound(s), whether it would be crystalline or not.In other words, the carrier should not substantially alter the form theactive compound(s) are. Nor should the carrier be otherwise incompatiblewith the form of the active compound(s), such as by producing anyundesirable biological effect or otherwise interacting in a deleteriousmanner with any other component(s) of the pharmaceutical composition.

The pharmaceutical compositions of this disclosure may be prepared bymethods know in the pharmaceutical formulation art, for example, seeRemington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company,Easton, Pa., 1990). In a solid dosage forms Compound (I) is admixed withat least one pharmaceutically acceptable excipient such as sodiumcitrate or dicalcium phosphate or (a) fillers or extenders, as forexample, starches, lactose, sucrose, glucose, mannitol, and silicicacid, (b) binders, as for example, cellulose derivatives, starch,alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c)humectants, as for example, glycerol, (d) disintegrating agents, as forexample, agar-agar, calcium carbonate, potato or tapioca starch, alginicacid, croscarmellose sodium, complex silicates, and sodium carbonate,(e) solution retarders, as for example paraffin, (f) absorptionaccelerators, as for example, quaternary ammonium compounds, (g) wettingagents, as for example, cetyl alcohol, and glycerol monostearate,magnesium stearate and the like (h) adsorbents, as for example, kaolinand bentonite, and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, tablets, andpills, the dosage forms may also comprise buffering agents.

Pharmaceutically acceptable adjuvants known in the pharmaceuticalformulation art may also be used in the pharmaceutical compositions ofthis disclosure. These include, but are not limited to, preserving,wetting, suspending, sweetening, flavoring, perfuming, emulsifying, anddispensing agents. Prevention of the action of microorganisms can beensured by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, sorbic acid, and the like. It may alsobe desirable to include isotonic agents, for example sugars, sodiumchloride, and the like. If desired, a pharmaceutical composition of thisdisclosure may also contain minor amounts of auxiliary substances suchas wetting or emulsifying agents, pH buffering agents, and antioxidants,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, and butylalted hydroxytoluene.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the active compound(s), or a crystallineform of the active compound(s), with, for example, suitablenon-irritating excipients or carriers such as cocoa butter,polyethyleneglycol or a suppository wax, which are solid at ordinarytemperatures but liquid at body temperature and therefore, melt while ina suitable body cavity and release the active component therein.

Because the active compound(s), or a crystalline form of the activecompound(s), is maintained during their preparation, solid dosage formsare preferred for the pharmaceutical composition of this disclosure.Solid dosage forms for oral administration, which includes capsules,tablets, pills, powders, and granules, are particularly preferred. Insuch solid dosage forms, the active compound(s) mixed with at least oneinert, pharmaceutically acceptable excipient (also known as apharmaceutically acceptable carrier). Administration of the activecompound(s), or a crystalline form of the active compound(s), in pureform or in an appropriate pharmaceutical composition, can be carried outvia any of the accepted modes of administration or agents for servingsimilar utilities. Thus, administration can be, for example, orally,nasally, parenterally (intravenous, intramuscular, or subcutaneous),topically, transdermally, intravaginally, intravesically,intracistemally, or rectally, in the form of solid, semi-solid,lyophilized powder, or liquid dosage forms, such as for example,tablets, suppositories, pills, soft elastic and hard gelatin capsules,powders, solutions, suspensions, or aerosols, or the like, preferably inunit dosage forms suitable for simple administration of precise dosages.One preferable route of administration is oral administration, using aconvenient dosage regimen that can be adjusted according to the degreeof severity of the disease-state to be treated.

General Preparation Methods of Crystalline Forms

Crystalline forms may be prepared by a variety of methods including, butnot limited to, for example, crystallization or recrystallization from asuitable solvent mixture; sublimation; growth from a melt; solid statetransformation from another phase; crystallization from a supercriticalfluid; and jet spraying. Techniques for crystallization orrecrystallization of crystalline forms of a solvent mixture include, butare not limited to, for example, evaporation of the solvent; decreasingthe temperature of the solvent mixture; crystal seeding of asupersaturated solvent mixture of the compound and/or salt thereof;crystal seeding a supersaturated solvent mixture of the compound and/ora salt from thereof; freeze drying the solvent mixture; and addingantisolvents (countersolvents) to the solvent mixture. High throughputcrystallization techniques may be employed to prepare crystalline formsincluding polymorphs.

Crystals of drugs, including polymorphs, methods of preparation, andcharacterization of drug crystals are discussed in Solid-State Chemistryof Drugs, S. R. Byrn, R. R. Pfeiffer, and J. G. Stowell, 2^(nd) Edition,SSCI, West Lafayette, Ind. (1999).

In a crystallization technique in which solvent is employed, thesolvent(s) are typically chosen based on one or more factors including,but not limited to, for example, solubility of the compound;crystallization technique utilized; and vapor pressure of the solvent.Combinations of solvents may be employed. For example, the compound maybe solubilized in a first solvent to afford a solution to whichantisolvent is then added to decrease the solubility of the Compound(I)n the solution and precipitate the formation of crystals. Anantisolvent is a solvent in which a compound has low solubility.

In one method that can be used in preparing crystals, Compound (I),Compound (II) and/or Compound (III) can be suspended and/or stirred in asuitable solvent to afford a slurry, which may be heated to promotedissolution. The term “slurry”, as used herein, means a saturatedsolution of the compound, wherein such solution may contain anadditional amount of compound to afford a heterogeneous mixture ofcompound and solvent at a given temperature.

Seed crystals may be added to any crystallization mixture to promotecrystallization. Seeding may be employed to control growth of aparticular polynorph and/or to control the particle size distribution ofthe crystalline product. Accordingly, calculation of the amount of seedsneeded depends on the size of the seed available and the desired size ofan average product particle as described, for example, in ProgrammedCooling Batch Crystallizers,” J. W. Mullin and J. Nyvlt, ChemicalEngineering Science, 1971, 26, 3690377. In general, seeds of small sizeare needed to effectively control the growth of crystals in the batch.Seeds of small size may be generated by sieving, milling, or micronizinglarge crystals, or by microcrystallizing a solution. In the milling ormicronizing of crystals, care should be taken to avoid changingcrystallinity from the desired crystalline form (i.e., changing to anamorphous or other polymorphic form).

A cooled crystallization mixture may be filtered under vacuum and theisolated solid product washed with a suitable solvent, such as, forexample, cold recrystallization solvent. After being washed, the productmay be dried under a nitrogen purge to afford the desired crystallineform. The product may be analyzed by a suitable spectroscopic oranalytical technique including, but not limited to, for example,differential scanning calorimetry (DSC); x-ray powder diffraction(XRPD); and thermogravimetric analysis (TGA) to assure the crystallineform of the compound has been formed. The resulting crystalline form maybe produced in an amount greater than about 70 wt. % isolated yield,based on the weight of the compound originally employed in thecrystallization procedure, and preferably greater than about 90 wt. %isolated yield. Optionally, the product may be delumped by beingcompiled or passed through mesh screen.

The features and advantages of this disclosure may be more readilyunderstood by those of ordinary skill in the art upon reading thefollowing detailed description. It is to be appreciated that certainfeatures of the invention that are, for clarity reasons, described aboveand below in the context of separate embodiments, may also be combinedto form a single embodiment. Conversely, various features of thisdisclosure that are, for brevity reasons, described in the context of asingle embodiment, may also be combined so as to form sub-combinationsthereof. The disclosure is further illustrated by the followingexamples, which are not to be construed as limiting the disclosure inscope or spirit to the specific procedures described in them.

The definitions set forth herein take precedence over definitions setforth in any patent, patent application, and/or patent applicationpublication incorporated herein by reference. All measurements aresubject to experimental error and are within the spirit of theinvention.

As used herein, “amorphous” refers to a solid form of a molecule and/orion that is not crystalline. An amorphous solid does not display adefinitive X-ray diffraction pattern with sharp maxima.

As used herein, the term “substantially pure” means the crystalline formof Compound (I) referred to contains at least about 90 wt. % based onthe weight of such crystalline form. The term “at least about 90 wt. %,”while not intending to limit the applicability of the doctrine ofequivalents to the scope of the claims, includes, but is not limited to,for example, about 90, about 91, about 92, about 93, about 94, about 95,about 96, about 97, about 98, about 99 and about 100% wt. %, based onthe weight of the crystalline form referred to. The remainder of thecrystalline form of Compound (I) may comprise other Form(s) of Compound(I) and/or reaction impurities and/or processing impurities that arise,for example, when the crystalline form is prepared. The presence ofreaction impurities and/or processing impurities may be determined byanalytical techniques known in the art, such as, for example,chromatography, nuclear magnetic resonance spectroscopy, massspectroscopy, and/or infrared spectroscopy.

PREPARATIVE EXAMPLES Example 1: Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt Thereof (Compound (I))

The synthetic route used for the preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideand the (L)-malate salt thereof is depicted in Scheme 1:

The process shown in Scheme 1 is described in more detail below.

1.1 Preparation of 4-Chloro-6,7-dimethoxy-quinoline

A reactor was charged sequentially with 6,7-dimethoxy-quinoline-4-ol (1L, 10.0 kg) and acetonitrile (64.0 L). The resulting mixture was heatedto approximately 65° C. and phosphorus oxychloride (POCl₃, 50.0 kg) wasadded. After the addition of POCl₃, the temperature of the reactionmixture was raised to approximately 80° C. The reaction was deemedcomplete (approximately 9.0 hours) when <2% of the starting materialremained (in process high-performance liquid chromatography [HPLC]analysis). The reaction mixture was cooled to approximately 10° C. andthen quenched into a chilled solution of dichloromethane (DCM, 238.0kg), 30% NH₄OH (135.0 kg), and ice (440.0 kg). The resulting mixture waswarmed to approximately 14° C., and phases were separated. The organicphase was washed with water (40.0 kg) and concentrated by vacuumdistillation with the removal of solvent (approximately 190.0 kg).Methyl-t-butyl ether (MTBE, 50.0 kg) was added to the batch, and themixture was cooled to approximately 10° C., during which time theproduct crystallized out. The solids were recovered by centrifugation,washed with n-heptane (20.0 kg), and dried at approximately 40° C. toafford the title compound (8.0 kg).

1.2 Preparation of 6,7-Dimethyl-4-(4-nitro-phenoxy)-quinoline

A reactor was sequentially charged with 4-chloro-6,7-dimethoxy-quinoline(8.0 kg), 4 nitrophenol (7.0 kg), 4 dimethylaminopyridine (0.9 kg), and2,6 lutidine (40.0 kg). The reactor contents were heated toapproximately 147° C. When the reaction was complete (<5% startingmaterial remaining as determined by in process HPLC analysis,approximately 20 hours), the reactor contents were allowed to cool toapproximately 25° C. Methanol (26.0 kg) was added, followed by potassiumcarbonate (3.0 kg) dissolved in water (50.0 kg). The reactor contentswere stirred for approximately 2 hours. The resulting solid precipitatewas filtered, washed with water (67.0 kg), and dried at 25° C. forapproximately 12 hours to afford the title compound (4.0 kg).

1.3 Preparation of 4-(6,7-Dimethoxy-quinoline-4-yloxy)-phenylamine

A solution containing potassium formate (5.0 kg), formic acid (3.0 kg),and water (16.0 kg) was added to a mixture of6,7-dimethoxy-4-(4-nitro-phenoxy)-quinoline (4.0 kg), 10% palladium oncarbon (50% water wet, 0.4 kg) in tetrahydrofuran (40.0 kg) that hadbeen heated to approximately 60° C. The addition was carried out suchthat the temperature of the reaction mixture remained approximately 60°C. When the reaction was deemed complete as determined using in-processHPLC analysis (<2% starting material remaining, typically 15 hours), thereactor contents were filtered. The filtrate was concentrated by vacuumdistillation at approximately 35° C. to half of its original volume,which resulted in the precipitation of the product. The product wasrecovered by filtration, washed with water (12.0 kg), and dried undervacuum at approximately 50° C. to afford the title compound (3.0 kg; 97%AUC).

1.4 Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarboxylicacid

Triethylamine (8.0 kg) was added to a cooled (approximately 4° C.)solution of commercially available cyclopropane-1,1-dicarboxylic acid (21, 10.0 kg) in THF (63.0 kg) at a rate such that the batch temperaturedid not exceed 10° C. The solution was stirred for approximately 30minutes, and then thionyl chloride (9.0 kg) was added, keeping the batchtemperature below 10° C. When the addition was complete, a solution of4-fluoroaniline (9.0 kg) in THF (25.0 kg) was added at a rate such thatthe batch temperature did not exceed 10° C. The mixture was stirred forapproximately 4 hours and then diluted with isopropyl acetate (87.0 kg).This solution was washed sequentially with aqueous sodium hydroxide (2.0kg dissolved in 50.0 L of water), water (40.0 L), and aqueous sodiumchloride (10.0 kg dissolved in 40.0 L of water). The organic solutionwas concentrated by vacuum distillation followed by the addition ofheptane, which resulted in the precipitation of solid. The solid wasrecovered by centrifugation and then dried at approximately 35° C. undervacuum to afford the title compound. (10.0 kg).

1.5 Preparation of 1-(4-Fluoro-phenylcarbamoyl)-cyclopropanecarbonylchloride

Oxalyl chloride (1.0 kg) was added to a solution of1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarboxylic acid (2.0 kg) in amixture of THF (11 kg) and N, N-dimethylformamide (DMF; 0.02 kg) at arate such that the batch temperature did not exceed 30° C. This solutionwas used in the next step without further processing.

1.6 Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

The solution from the previous step containing1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl chloride was added toa mixture of 4-(6,7-dimethoxy-quinoline-4-yloxy)-phenylamine (3.0 kg)and potassium carbonate (4.0 kg) in THF (27.0 kg) and water (13.0 kg) ata rate such that the batch temperature did not exceed 30° C. When thereaction was complete (in typically 10 minutes), water (74.0 kg) wasadded. The mixture was stirred at 15-30° C. for approximately 10 hours,which resulted in the precipitation of the product. The product wasrecovered by filtration, washed with a premade solution of THE (11.0 kg)and water (24.0 kg), and dried at approximately 65° C. under vacuum forapproximately 12 hours to afford the title compound (free base, 5.0 kg).¹HNMR (400 MHz, d₆-DMSO): δ 10.2 (s, 1H), 10.05 (s, 1H), 8.4 (s, 1H),7.8 (m, 2H), 7.65 (m, 2H), 7.5 (s, 1H), 7.35 (s, 1H), 7.25 (m, 2H), 7.15(m, 2H), 6.4 (s, 1H), 4.0 (d, 6H), 1.5 (s, 4H). LC/MS: M+H=502.

1.7 Preparation ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(L) malate salt (Compound (I))

A solution of (L)-malic acid (2.0 kg) in water (2.0 kg) was added to asolution of Cyclopropane-1,1-dicarboxylic acid[4-(6,7-dimethoxy-quinoline-4-yloxy)-phenyl]-amide(4-fluoro-phenyl)-amide free base (15, 5.0 kg) in ethanol, maintaining abatch temperature of approximately 25° C. Carbon (0.5 kg) and thiolsilica (0.1 kg) were then added, and the resulting mixture was heated toapproximately 78° C., at which point water (6.0 kg) was added. Thereaction mixture was then filtered, followed by the addition ofisopropanol (38.0 kg), and was allowed to cool to approximately 25° C.The product was recovered by filtration and washed with isopropanol(20.0 kg) and dried at approximately 65° C. to afford Compound (I) (5.0kg).

Example 2: Preparation of Crystalline Compound (I), Form N-1

A solution was prepared by adding tetrahydrofuran (12 mL/g-bulk-LR(limiting reagent); 1.20 L) andN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(100 g; 1.00 equiv; 100.00 g) and (L)-malic acid (1.2 equiv (molar);32.08 g) to a 1 L reactor. Water (0.5317 mL/g-bulk-LR; 53.17 mL) wasadded and the solution was heated to 60° C. and maintained at thattemperature for one hour until the solids were fully dissolved. Thesolution was passed through a Polish Filter.

At 60° C., acetonitrile (12 mL/g-bulk-LR; 1.20 L) was added over aperiod of 8 hours. The solution was held at 60° C. for 10 hours. Thesolution was then cooled to 20° C. and held for 1 hour. The solids werefiltered and washed with acetonitrile (12 mL/g-bulk-LR; 1.20 L). Thesolids were dried at 60° C. (25 mm Hg) for 6 hours to afford Compound(I), Form N-1 (108 g; 0.85 equiv; 108.00 g; 85.22% yield) as a whitecrystalline solid.

Example 3: Alternate Preparation of Crystalline Compound (I), Form N-1

A solution was prepared with 190 mL tetrahydrofuran (110 mL), methylisobutyl ketone, and 29 mL water. Next, 20 mL of this solution weretransferred into an amber bottle, and then saturated by addingN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(L)-malate until a thick slurry formed, and aging for at least 2 h withstirring at room temperature. The solids were removed by filtrationthrough a Buchner funnel, rendering a clear saturated solution.

Separately, a powder blend was made with known amounts of two batches ofCompound (I): (1) 300 mg of batch 1, which contained approximately 41%Compound (I), Form N-1 and 59% Compound (I), Form N-2 by Ramanspectroscopy analysis, and (2) 200 mg of batch 2, which had a XPRDpattern similar to Compound (I), Form N-2.

The Compound (I), Form N-1 and Compound (I), Form N-2 powder blend wasadded into the saturated solution, and the slurry was aged undermagnetic stirring at room temperature for 25 days. The slurry was thensampled and filtered through a Buchner funnel to obtain 162 mg of wetcake. The wet cake was dried in a vacuum oven at 45° C. to afford 128 mgof crystalline Compound (I) in the N-1 form.

Example 4: Preparation of Crystalline Compound (I), Form N-2 4.1Preparation of Crystalline Compound (I), Form N-2 Seed Crystals

A solution was prepared by combining 20 ml of acetone and 300 mg offreebaseN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidein a 25 ml screw capped vial. Next, 0.758 ml of a 0.79M (L)-malic acidstock solution was added to the vial with magnetic stirring. Thesolution was then left stirring for 24 hr at ambient temperature. Thesample was then suction filtered with 0.45 μm PTFE filter cartridge anddried in vacuo at ambient temperature overnight.

4.2 Preparation of Crystalline Compound (I), Form N-2

To a reactor were addedN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(48 g; 1.00 equiv; 48.00 g) and tetrahydrofuran (16.5 mL/g-bulk-LR;792.00 mL). The water content was adjusted to 1 wt % water. The solutionwas heated to 60° C. Once dissolved, the solution was passed through apolish filter to provide the first solution.

In a separate reactor, (L)-malic acid (1.2 equiv (molar); 15.40 g) wasdissolved into methyl isobutyl ketone (10 mL/g-bulk-LR; 480.00 mL) andtetrahydrofuran (1 mL/g-bulk-LR; 48.00 mL). Next, 50 mL of the (L)-malicacid solution was added to the first solution at 50° C. Seed crystalswere added (1%, 480 mg) and the malic acid solution was added at 50° C.dropwise via an addition funnel (1.3 ml/min (3 h)). The slurry was heldat 50° C. for 18 h and then was cooled to 25° C. over 30 min. The solidswere filtered, and washed with 20% tetrahydrofuran/methyl isobutylketone (10V, 480 ml). The solids were dried under vacuum at 60° C. for 5h to afford Compound (I) (55.7 g; 0.92 equiv; 55.70 g; 91.56% yield) asan off-white crystalline solid.

Example 5: Preparation of Crystalline Compound (III), Form N-1

A one ml aliquot (DL)-malic acid salt ofN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,slurried in tetrahydrofuran (THF), was heated to 60° C. on a hot-platein a half-dram vial. Next, tetrahydrofuran was added drop-wise until analmost clear solution was obtained. The vial was capped, removed fromthe hot plate and equilibrated at ambient temperature without agitation.Crystallization was apparent after several hours and the solution wasallowed to stand overnight to allow completion. Several droplets of theresulting slurry were placed on a glass slide for microscopic analysis.The crystalline material consisted of many elongated plates ranging upto 60 microns in the longest dimension.

Alternate Preparation of Crystalline Compound (III), Form N-1

To a reactor were addedN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(15 g; 1.00 equiv; 15.00 g) and tetrahydrofuran (16.5 mL/g-bulk-LR;792.00 mL). The water content was adjusted to 1 wt % water. The solutionwas heated to 60° C. Once dissolved, the solution was passed through apolish filter to provide the first solution.

In a separate reactor, (DI)-malic acid (1.2 equiv (molar); 4.53 g) wasdissolved into methyl isobutyl ketone (8 mL/g-bulk-LR; 120.00 mL) andtetrahydrofuran (1 mL/g-bulk-LR; 15.00 mL). Next, 20 mL of the solutionwas added to the first solution at 50° C. The malic acid solution wasadded at 50° C. dropwise via an addition funnel (1.3 ml/min (3 h)). Theslurry was held at 50° C. for 18 h and then was cooled to 25° C. over 30min. The solids were filtered, and washed with 20% THF/MIBK (10V, 150mL). The solids were dried under vacuum at 60° C. for 5 h to affordCompound (III) (15.52 g; 86.68% yield) as an off-white solid.

Example 6: Preparation of Amorphous Compound (I)

A solution was prepared with 5 g ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(L)-malate and 250 mL of a 1:1 (v:v) mixture of methanol anddichloromethane. The hazy solution was filtered through a 0.45 micronfilter to yield a clear, yellowish solution. The solution was pumpedthrough the spray dryer nozzle at a rate of 12.9 cc/min, and wasatomized by nitrogen gas fed at a rate of 10.911 min. The temperature atthe inlet of the cyclone was set to 65° C. to dry the wet droplets. Dryamorphous powder (1.5 g) was collected (yield=30%).

CHARACTERIZATION EXAMPLES

I. NMR Spectra in Dimethyl Sulfoxide Solution

I.1 Compound (I), Form N-1

¹H NMR (400 MHz, d₆-DMSO): δ 1.48 (s, 1H), 2.42-2.48 (m, 1H), 2.60-2.65(m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30 (dd, 1H, J=5, 8 Hz), 6.44 (d, 1H,J=5 Hz, 1H), 7.12-7.19 (m, 2H), 7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51(s, 1H), 7.63-7.68 (m, 2H), 7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08(s, 1H), 10.21 (s, 1H).

¹³C NMR (d₆-DMSO): 15.36, 31.55, 55.64, 55.67, 66.91, 99.03, 102.95,107.66, 114.89, 115.07, 115.11, 121.17, 122.11, 122.32, 122.39, 135.15,136.41, 146.25, 148.7, 149.28, 149.38, 152.54, 157.03, 159.42, 160.02,168.07, 171.83, 174.68.

I.2 Compound (I), Form N-2

¹H NMR (400 MHz, d₆-DMSO): δ 1.48 (s, 1H), 2.42-2.48 (m, 1H), 2.60-2.65(m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30 (dd, 1H, J=5, 8 Hz), 6.44 (d, J=5Hz, 1H), 7.12-7.19 (m, 2H), 7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s,1H), 7.63-7.68 (m, 2H), 7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s,1H), 10.21 (s, 1H).

¹³C NMR (d₆-DMSO): 15.36, 31.55, 55.64, 55.67, 66.91, 99.03, 102.95,107.66, 114.89, 115.07, 115.11, 121.17, 122.11, 122.32, 122.39, 135.15,136.41, 146.25, 148.7, 149.28, 149.38, 152.54, 157.03, 159.42, 160.02,168.07, 171.83, 174.68.

I.3 Compound (III), Form N-1

¹H NMR (400 MHz, d₆-DMSO): δ 1.48 (s, 1H), 2.42-2.48 (m, 1H), 2.60-2.65(m, 1H), 3.93-3.96 (m, 6H), 4.25-4.30 (dd, 1H, J=5, 8 Hz), 6.44 (d, J=5Hz, 1H), 7.12-7.19 (m, 2H), 7.22-7.26 (m, 2H), 7.40 (s, 1H), 7.51 (s,1H), 7.63-7.68 (m, 2H), 7.76-7.80 (m, 2H), 8.46-8.49 (m, 1H), 10.08 (s,1H), 10.21 (s, 1H).

¹³C NMR (d₆-DMSO): 15.36, 31.55, 55.64, 55.67, 66.91, 99.03, 102.95,107.66, 114.89, 115.07, 115.11, 121.17, 122.11, 122.32, 122.39, 135.15,136.41, 146.25, 148.7, 149.28, 149.38, 152.54, 157.03, 159.42, 160.02,168.07, 171.83, 174.68.

Characterization of Solid State Forms ofN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,malate

II. Powder X-Ray Diffraction (XRPD) Studies

X-Ray Powder Diffraction (XRPD) patterns were collected on a Bruker AXSC2 GADDS diffractometer equipped with an automated XYZ stage, laservideo microscope for auto-sample positioning and a HiStar 2-dimensionalarea detector. The radiation source used was copper (Cu Kα=1.5406 Å),wherein the voltage was set at 40 kV and the current was set at 40 mA,X-ray optics consists of a single Göbel multilayer mirror coupled with apinhole collimator of 0.3 mm. The beam divergence, i.e. the effectivesize of the X-ray beam on the sample, was approximately 4 mm. A 0-0continuous scan mode was employed with a sample—detector distance of 20cm which gives an effective 20 range of 3.2°-29.8°. Samples run underambient conditions (from about 18° C. to about 25° C.) were prepared asflat plate specimens using powder as received without grinding.Approximately 1-2 mg of the sample was lightly pressed on a glass slideto obtain a flat surface. Typically the sample would be exposed to theX-ray beam for 120 seconds. Beam divergence (i.e., effective size ofX-ray spot, gives a value of approximately 4 mm. Alternatively, thepowder samples were placed in sealed glass capillaries of 1 mm or lessin diameter; the capillary was rotated during data collection at asample-detector distance of 15 cm. Data were collected for 3≤2θ≤35° witha sample exposure time of at least 2000 seconds. The resultingtwo-dimensional diffraction arcs were integrated to create a traditional1-dimensional XRPD pattern with a step size of 0.02°2θ in the range of 3to 35°2θ±0.2°2θ. The software used for data collection was GADDS for WNT4.1.16 and the data were analyzed and presented using Diffrac Plus EVA v9.0.0.2 or v 13.0.0.2.

II.1 Compound (I), Form N-1

FIG. 1 shows the experimental XRPD pattern of crystalline Compound (I),Form N-1 acquired at room temperature (about 25° C.). A list of thepeaks are shown in Table 2, above. The 2θ values at 19.4, 21.5, 22.8,25.1, and 27.6 (±0.2°2θ) are useful for characterizing crystallineCompound (I), Form N-1. The entire list of peaks, or a subset thereof,may be sufficient to characterize crystalline Compound (I), Form N-1.

II.2 Compound (I), Form N-2

FIG. 8 shows the experimental XRPD pattern of crystalline Compound (I),Form N-2 acquired at room temperature (about 25° C.). A list of thepeaks are shown in Table 2, above. The 2θ values at 20.9 and 21.9(±0.2°2θ) are useful for characterizing crystalline Compound (I), FormN-2. The entire list of peaks, or a subset thereof, may be sufficient tocharacterize crystalline Compound (I), Form N-2.

II.3 Compound (III), Form N-1

FIG. 15 shows the experimental and the simulated XRPD pattern ofcrystalline Compound (III), Form N-1, acquired at 25° C. using aspinning capillary sample. A list of the peaks are shown in Table 2,above. The entire list of peaks, or a subset thereof, may be sufficientto characterize crystalline Compound (III), Form N-2.

II.4 Amorphous Compound (I)

FIG. 22 shows the experimental XRPD pattern of amorphous Compound (I)acquired at room temperature (about 25° C.). The spectra ischaracterized a broad peak and the absence of sharp peaks, which isconsistent with an amorphous material.

III. Single Crystal X-Ray Study for Compound (III), Form N-1

Data were collected on a Bruker-Nonius CAD4 serial diffractometer. Unitcell parameters were obtained through least-squares analysis of theexperimental diffractometer settings of 25 high-angle reflections.Intensities were measured using Cu Kα radiation (λ=1.5418 Å) at aconstant temperature with the 0-20 variable scan technique and werecorrected only for Lorentz-polarization factors. Background counts werecollected at the extremes of the scan for half of the time of the scan.Alternately, single crystal data were collected on a Bruker-Nonius KappaCCD 2000 system using Cu Kα radiation (λ=1.5418 Å). Indexing andprocessing of the measured intensity data were carried out with theHKL2000 software package (Otwinowski, Z. & Minor, W. (1997) inMacromolecular Crystallography, eds. Carter, W. C. Jr & Sweet, R. M.(Academic, NY), Vol. 276, pp. 307-326) in the Collect program suite(Collect Data collection and processing user interface: Collect: Datacollection software, R. Hooft, Nonius B. V., 1998). Alternately, singlecrystal data were collected on a Bruker-AXS APEX2 CCD system using Cu Kαradiation (λ=1.5418 Å). Indexing and processing of the measuredintensity data were carried out with the APEX2 software package/programsuite (APEX2 Data collection and processing user interface: APEX2 UserManual, v.27). When indicated, crystals were cooled in the cold streamof an Oxford cryo system (Oxford Cryosystems Cryostream cooler: J.Cosier and A. M. Glazer, J. Appl. Cryst., 1986, 19, 105) during datacollection.

The structures were solved by direct methods and refined on the basis ofobserved reflections using either the SDP software package (SDP,Structure Determination Package, Enraf-Nonius, Bohemia N.Y. 11716.Scattering factors, including f′ and f″, in the SDP software were takenfrom the “International Tables for Crystallography”, Kynoch Press,Birmingham, England, 1974; Vol IV, Tables 2.2A and 2.3.1) with minorlocal modifications or the crystallographic packages MAXUS (maXussolution and refinement software suite: S. Mackay, C. J. Gilmore, C.Edwards, M. Tremayne, N. Stewart, K. Shankland. maXus: a computerprogram for the solution and refinement of crystal structures fromdiffraction data) or SHELXTL (APEX2 Data collection and processing userinterface: APEX2 User Manual, v1.27).

The derived atomic parameters (coordinates and temperature factors) wererefined through full matrix least-squares. The function minimized in therefinements was Σ_(w)(|F_(o)|−|F_(c)|)². R is defined asΣ∥F_(o)|−|F_(c)∥/Σ|F_(o)| whileR_(w)=[Σ_(w)(|F_(o)|−|F_(c)|)²/Σ_(w)|F_(o)|²]^(1/2) where w is anappropriate weighting function based on errors in the observedintensities. Difference maps were examined at all stages of refinement.Hydrogens were introduced in idealized positions with isotropictemperature factors, but no hydrogen parameters were varied.

“Hybrid” simulated powder X-ray patterns were generated as described inthe literature (Yin. S.; Scaringe, R. P.; DiMarco, J.; Galella, M. andGougoutas, J. Z., American Pharmaceutical Review, 2003, 6,2, 80). Theroom temperature cell parameters were obtained by performing a cellrefinement using the CellRefine.xls program. Input to the programincludes the 2-theta position of ca. 10 reflections, obtained from theexperimental room temperature powder pattern; the corresponding Millerindices, hkl, were assigned based on the single-crystal data collectedat low temperature. A new (hybrid) XRPD was calculated (by either of thesoftware programs, Alex or LatticeView) by inserting the molecularstructure determined at low temperature into the room temperature cellobtained in the first step of the procedure. The molecules are insertedin a manner that retains the size and shape of the molecule and theposition of the molecules with respect to the cell origin, but, allowsintermolecular distances to expand with the cell.

A single crystal, measuring 40×30×10 microns, was selected from theslurry of crystals described in Example 5 for single crystal diffractionanalysis. The selected crystal was affixed to a thin glass fiber with asmall amount of a light grease, and mounted at room temperature on aBruker ApexII single crystal diffractometer equipped with a rotatingcopper anode.

Crystalline Compound (III), From N-1 is characterized by unit cellparameters approximately equal to those reported in Table 4. The unitcell parameters were measured at a temperature of about 25° C.

TABLE 4   a = 14.60 Å b = 5.20 Å c = 39.09 Å α = 90.0° β = 90.4° γ =90.0° Space group: P2₁/n Molecules of Compound (I)/unit cell: 4 Volume =2969 Å³

Structure solution and refinement were routine in the monoclinic spacegroup, P2₁/n, with four formula units in the unit cell. The structurecontains cations ofN-(4-{[6,7-bis(methyloxy)-quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,protonated at the quinoline nitrogen atom, and singly ionized malic acidanions, in a1:1 ratio. Further, the crystal contained a1:1 ratio of(L)-malic acid ions to (D)-malic acid ions. Table 5

fractional atomic coordinates for Compound (III), Form N-1 calculated ata temperature of about 25° C.

Based on the single crystal X-ray data, crystalline Compound (III), FormN-1 may be characterized by a simulated powder x-ray diffraction (XRPD)pattern substantially in accordance with the simulated pattern shown inFIG. 15 and/or by an observed XRPD pattern substantially in accordancewith the experimental pattern shown in FIG. 15.

TABLE 5 Fractional Atomic Coordinates for Compound (III), Form N-1Calculated at a Temperature of about 25° C. Atom X Y Z O1 0.30601−0.52166 0.22875 O2 0.29518 0.12504 0.09391 O3 0.19041 −0.53232 0.18147F5 −0.07307 2.12170 −0.08811 O6 0.18186 1.20500 −0.03241 O7 0.571370.22739 0.23473 O8 0.58700 −0.17911 0.24998 O9 0.41742 0.76377 −0.04319N10 0.28649 0.82210 −0.01420 O11 0.87391 0.22086 0.31241 N12 0.468870.17029 0.17613 C13 0.29647 0.64886 0.01247 C14 0.31416 1.08187 −0.06304C15 0.33900 −0.02207 0.14761 N16 0.20651 1.40640 −0.08267 C17 0.40079−0.01723 0.17602 C18 0.29743 0.29956 0.06604 C19 0.00418 1.80556−0.05680 C20 0.11925 1.73626 −0.11097 C21 0.22556 1.24019 −0.05791 C220.39150 −0.17467 0.20389 C23 0.22558 0.63870 0.03619 C24 0.62714 0.395650.29760 C25 0.34591 0.87438 −0.03961 C26 0.36467 −0.51389 0.25773 C270.26562 −0.20277 0.14859 C28 0.35380 0.15272 0.12054 C29 0.07365 1.60604−0.05443 C30 0.04897 1.92890 −0.11212 C31 0.73841 0.04517 0.28641 C320.32089 −0.35160 0.20385 C33 0.36641 0.29052 0.04302 C34 0.42458 0.322720.12143 C35 0.11723 −0.54030 0.15742 C36 0.12933 1.59042 −0.08228 C37−0.00344 1.93494 −0.08547 C38 0.36439 0.47245 0.01586 C39 0.590400.05797 0.25625 C40 0.25712 −0.35516 0.17574 C41 0.63543 0.13842 0.29041C42 0.22703 0.46640 0.06306 C43 0.34559 1.01717 −0.10021 C44 0.393121.20834 −0.08137 C45 0.48224 0.32340 0.15059 O46 0.77400 0.04784 0.34652C47 0.79349 0.09920 0.31966 H10 0.22646 0.91057 −0.01479 H16 0.247901.42164 −0.10317 H19 −0.04176 1.82973 −0.03893 H20 0.16347 1.73025−0.13083 H22 0.43179 −0.17902 0.22447 H23 0.17093 0.73524 0.03244 H270.21953 −0.24212 0.12962 H29 0.07954 1.50390 −0.03492 H30 0.046712.05817 −0.13354 H33 0.41851 0.16255 0.04395 H34 0.43433 0.41859 0.10106H38 0.41440 0.45648 −0.00227 H41 0.61062 0.02238 0.31086 H42 0.177520.45794 0.07911 H45 0.53033 0.44239 0.15049 H31a 0.76754 0.12071 0.26693H31b 0.74726 −0.15247 0.28137 H43a 0.30237 1.06909 −0.12187 H43b 0.368680.85693 −0.10836 H44a 0.45563 1.18725 −0.07495 H44b 0.38932 1.39942−0.08846 H26a 0.35958 −0.37184 0.27147 H26b 0.42813 −0.55605 0.25348H26c 0.34954 −0.66814 0.27571 H35a 0.08189 −0.39941 0.15398 H35b 0.06671−0.68838 0.16269 H35c 0.13276 −0.61095 0.13323 H11 0.88836 0.219260.28968 H12 0.50720 0.16494 0.19477 H24 0.61522 0.45898 0.27789

IV. Solid State Nuclear Magnetic Resonance (SSNMR)

All solid-state C-13 NMR measurements were made with a Bruker DSX-400,400 MHz NMR spectrometer. High resolution spectra were obtained usinghigh-power proton decoupling and the TPPM pulse sequence and rampamplitude cross-polarization (RAMP-CP) with magic-angle spinning (MAS)at approximately 12 kHz (A. E. Bennett et al, J. Chem. Phys., 1995, 103,6951), (G. Metz, X. Wu and S. O. Smith, J. Magn. Reson. A, 1994, 110,219-227). Approximately 70 mg of sample, packed into a canister-designzirconia rotor was used for each experiment. Chemical shifts (6) werereferenced to external adamantane with the high frequency resonancebeing set to 38.56 ppm (W. L. Earl and D. L. VanderHart, J. Magn.Reson., 1982, 48, 35-54).

IV.1 Compound (I), Form N-1

The solid state ¹³C NMR spectrum of crystalline Compound (I), Form N-1is shown in FIG. 2. The entire list of peaks, or a subset thereof, maybe sufficient to characterize crystalline Compound (I), Form N-1.

SS ¹³C NMR Peaks: 18.1, 20.6, 26.0, 42.9, 44.5, 54.4, 55.4, 56.1, 70.4,99.4, 100.1, 100.6, 114.4, 114.9, 115.8, 119.6, 120.1, 121.6, 123.2,124.1, 136.4, 138.6, 140.6, 145.4, 150.1, 150.9, 156.2, 157.4, 159.4,164.9, 167.1, 170.8, 175.7, and 182.1 ppm, ±0.2 ppm.

FIG. 3 shows the solid state ¹⁵N NMR spectrum of crystalline Compound(I), Form N-1. The spectrum shows peaks at 118.6, 119.6, 120.7, 134.8,167.1, 176.0, and 180 ppm, ±0.2 ppm. The entire list of peaks, or asubset thereof, may be sufficient to characterize crystalline Compound(I), Form N-1.

FIG. 4 shows the solid state ¹⁹F NMR spectrum of crystalline Compound(I), Form N-1. The spectrum shows a peak at −121.6, −120.8, and −118.0ppm, ±0.2 ppm.

IV.2 Compound (I), Form N-2

The solid state ¹³C NMR spectrum of crystalline Compound (I), Form N-2is shown in FIG. 9. The entire list of peaks, or a subset thereof, maybe sufficient to characterize crystalline Compound (I), Form N-2.

SS ¹³C NMR Peaks: 20.5, 21.8, 23.0, 25.9, 26.4, 38.0, 41.7, 54.7, 55.8,56.2, 56.6, 69.7, 99.4, 100.0, 100.4, 100.8, 102.3, 114.5, 115.5, 116.7,119.0, 120.2, 121.1, 121.2, 122.1, 122.9, 124.5, 136.0, 137.3, 138.1,138.9, 139.5, 140.2, 144.9, 145.7, 146.1, 150.7, 156.7, 157.7, 159.6,159.7, 165.1, 167.0, 168.0, 171.5, 177.3, 179.3, 180.0, and 180.3 ppm,±0.2 ppm.

FIG. 10 shows the solid state ¹⁵N NMR spectrum of crystalline Compound(I), Form N-2. The spectrum shows peaks at 118.5, 120.8, 135.1, 167.3,and 180.1 ppm, ±0.2 ppm. The entire list of peaks, or a subset thereof,may be sufficient to characterize crystalline Compound (I), Form N-2.

FIG. 11 shows the solid state ¹⁹F NMR spectrum of crystalline Compound(I), Form N-2. The spectrum shows peaks at −121.0 and −119.1 ppm, ±0.2ppm. Those peaks, individually or together, may be sufficient tocharacterize crystalline Compound (I), Form N-2.

IV.3 Compound (III), Form N-1

The solid state ¹³C NMR spectrum of crystalline Compound (III), Form N-1is shown in FIG. 16. The entire list of peaks, or a subset thereof, maybe sufficient to characterize crystalline Compound (III), Form N-1.

SS ¹³C NMR Peaks: 20.8, 26.2, 44.8, 55.7, 70.7, 100.4, 101.0, 114.7,115.2, 116.0, 119.7, 120.4, 121.6, 124.4, 136.9, 138.9, 141.1, 145.7,150.3, 156.5, 157.6, 159.6, 165.2, 167.4, 171.2, 176.3, and 182.1 ppm,±0.2 ppm.

FIG. 17 shows the solid state ¹⁵N NMR spectrum of crystalline Compound(III), Form N-1. The spectrum shows peaks at 119.6, 134.7, and 175.5ppm, ±0.2 ppm. The entire list of peaks, or a subset thereof, may besufficient to characterize crystalline Compound (III), Form N-1.

FIG. 18 shows the solid state ¹⁹F NMR spectrum of crystalline Compound(III), Form N-1. The spectrum shows a peak at −120.5 ppm, ±0.2 ppm.

IV.4 Compound (I), Amorphous

FIG. 23 shows the solid state ¹³C NMR spectrum of amorphous Compound(I). The entire list of peaks, or a subset thereof, may be sufficient tocharacterize amorphous Compound (I).

SS ¹³C NMR Peaks (ppm): 12.2, 17.8, 20.3, 21.8, 27.2, 33.8, 41.7, 56.9,69.9, 99.9, 102.2, 115.6, 122.2, 134.4, 137.8, 142.9, 149.1, 150.9,157.3, 159.7, 167.0, 171.7, 173.1, 177.4, and 179.5 ppm, ±0.2 ppm.

FIG. 24 shows the solid state ¹⁵N NMR spectrum of amorphous Compound(I). The spectrum shows peaks at 120.8, 131.8, 174.7, and 178.3 ppm,±0.2 ppm. The entire list of peaks, or a subset thereof, may besufficient to characterize amorphous Compound (I).

FIG. 25 shows the solid state 19F NMR spectrum of amorphous Compound(I). The spectrum shows a peak at −118.9 ppm, ±0.2 ppm.

V. Thermal Characterization Measurements

Thermal Gravimetric Analysis (TGA)

The TGA measurements were performed in a TA Instruments™ model Q500 or2950, employing an open pan setup. The sample (about 10-30 mg) wasplaced in a platinum pan previously tared. The weight of the sample wasmeasured accurately and recorded to a thousand of a milligram by theinstrument. The furnace was purged with nitrogen gas at 100 mL/min. Datawere collected between room temperature and 300° C. at 10° C./minheating rate.

Differential Scanning Calorimetry (DSC) Analysis

DSC measurements were performed in a TA Instruments™ model Q2000, Q1000or 2920, employing an open pan setup. The sample (about 2-6 mg) wasweighed in an aluminum pan and recorded accurately recorded to ahundredth of a milligram, and transferred to the DSC. The instrument waspurged with nitrogen gas at 50 mL/min. Data were collected between roomtemperature and 300° C. at 10° C./min heating rate. The plot was madewith the endothermic peaks pointing down.

V.1 Compound (I), Form N-1

FIG. 5 shows the TGA thermogram for crystalline Compound (I), Form N-1,which shows a weight loss of approximately 0.4 weight % at a temperatureof 170° C.

FIG. 6 shows the DSC thermogram for crystalline Compound (I), Form N-1,which showed a melting point of approximately 187° C.

V.2 Compound (I), Form N-2

FIG. 12 shows the TGA thermogram for crystalline Compound (I), Form N-2,which shows a weight loss of approximately 0.1 weight % at a temperatureof 170° C.

FIG. 13 shows the DSC thermogram for crystalline Compound (I), Form N-2,which showed a melting point of approximately 186° C.

V.3 Compound (III), Form N-1

FIG. 19 shows the TGA thermogram for crystalline Compound (III), FormN-1, which shows a weight loss of approximately 0.2 weight % at atemperature of 170° C.

FIG. 20 shows the DSC thermogram for crystalline Compound (III), FormN-1, which showed a melting point of approximately 186° C.

V.2 Compound (I), Amorphous

FIG. 26 shows the DSC for crystalline Compound (I).

VI. Moisture Vapor Isotherm Measurements

Moisture sorption isotherms were collected in a VTI SGA-100 SymmetricVapor Analyzer using approximately 10 mg of sample. The sample was driedat 60° C. until the loss rate of 0.0005 wt %/min was obtained for 10minutes. The sample was tested at 25° C. and 3 or 4, 5, 15, 25, 35, 45,50, 65, 75, 85, and 95% RH. Equilibration at each RH was reached whenthe rate of 0.0003 wt %/min for 35 minutes was achieved or a maximum of600 minutes.

VI.1 Compound (I), Form N-1

FIG. 7 shows the moisture vapor isotherm of crystalline Compound (I),Form N-1.

VI.2 Compound (I), Form N-1

FIG. 14 shows the moisture vapor isotherm of crystalline Compound (I),Form N-2.

VI.3 Compound (III), Form N-1

FIG. 21 shows the moisture vapor isotherm of crystalline Compound (III),Form N-1.

VI.4 Compound (I), Amorphous

FIG. 27 shows the moisture vapor isotherm of amorphous Compound (I).

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive. The scope of the invention should, therefore, bedetermined not with reference to the above description, but shouldinstead be determined with reference to the following appended claims,along with the full scope of equivalents to which such claims areentitled.

1-15. (canceled)
 16. A pharmaceutical composition comprising theN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt, wherein said salt iscrystalline; and a pharmaceutically acceptable excipient.
 17. Apharmaceutical composition comprising theN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt, wherein said salt is the(DL)-malate salt and wherein said salt is crystalline; and apharmaceutically acceptable excipient.
 18. A pharmaceutical compositioncomprising theN-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxylphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, malate salt, wherein said salt is the(L)-malate salt or (D)-malate salt and wherein said salt is crystalline;and a pharmaceutically acceptable excipient.